AKNOWLEDGEMENT

We place on record our thanks to Dr. Prof. Alok Gupta, Director, Sherwood College of Pharmacy Barabanki. We also place our thanks to Mr. Arvind Kumar, Mr. Rakesh Singh and Mrs. Preeti Aeron, faculty of pharmacy. We are also very grateful to our tour company for providing us a very memorable visit cum industrial visit to different MNCs. In the last, but not the least, I sincerely thank my parents, my teachers, all my batch mates for their support and assistance extended during the course of this project.

***********************

PREFACE The unprecedented pace of developments over the recent years in the field of drugs (medicine) as further emphasized the relevance of pharmaceuticals of health professionals.

In the regards of this project the main emphasis is laid on the production of tables. Tablet is a medicinal formulation made of a compressed powdered substance containing an active drug and excipients. Here we discuss about the detail study of the manufacturing of tablets, like Raw material, QA-QC for raw materials, granulation, drying, manufacturing of tablets, and coating, QA-QC for manufactured tablets, packaging and marketing. Thanks are due to my colleagues and respected faculty members for their valuable feedback and suggestions. We express our sincere gratitude to Prof. Alok Gupta director of faculty of pharmacy, and our respected faculty members for their keen interest and painstaking efforts in bringing this project in very short span of time.

************************

A research-driven, global, integrated pharmaceutical company. Glenmark is a leading player in the discovery of new molecules both NCEs (new chemical entity) and NBEs (new biological entity) with eight molecules in various stages of clinical development. The company has a significant presence in branded generics markets across emerging economies including India. Its subsidiary, Glenmark Generics Limited has a fast growing and robust US generics business. The subsidiary also markets APIs to regulated and semi-regulated countries. Glenmark employs nearly 6000 people in over 80 countries. It has twelve manufacturing facilities in four countries and has five R&D centres. Glenmark was chosen as the Best Pharma Company in the World SME and Best Company across emerging markets for 2008 by SCRIP, the largest selling and most respected pharmaceutical magazine in the world.

Contact address Glenmark House, HDO-Corporate Bldg, Wing-A, B.D.Sawant Marg, Chakala, Andheri (East) Mumbai, Maharashtra 400099 India Phone: +91 22 4018 9999 Fax: 91 22 6758 9986

Alkem Laboratories Ltd. was founded in 1974 by one of India's respected entrepreneurs, Shri Samprada Singh. In the last three and a half decades of its operations, Alkem has successfully emerged as a leading domestic Pharma major in and is rapidly multiplying its international footprint.
7

Alkem has carved out for itself, a special reputation in the field of sales and marketing. In India, the strength of Alkem's sales and marketing, along with its expertise in brand buildings are recognized widely and are considered as amongst the very best. Some of the biggest brands in the Indian Pharma market are the Alkem brands. The Alkem product portfolio encompasses a wide spectrum of therapeutic groups, ranging from Anti bacterials, NSAIDS, Gastro Enterology products, Gynaecology products, CNS and CVS products along with an impressive oncology range.

Contact address:CompanyName Contact Person

Address

Alkem Laboratories Ltd Mr. S. R. IYER

Alkem House, Adjacent to Matulya Centre, Senapati Bapat Marg, Lower Parel Mumbai, Maharashtra, India. 400 013 +91 - 22 - 39829999 +91 - 22 - 24952955
www.alkemlabs.com

Zip / Postal Code Telephone Fax Website

Incepted in year 2004, we are prominent manufacturer and exporter of generic medicines, pharmaceutical products and other health care products. We are anISO 9001-2000 certified company, manufacturing pharmaceutical drugs and medicines as per the processes laid down in WHO guidelines.

Our product range includes a wide var pharmaceutical tablet, foods supplement, pharmaceutical syrup, drop medicines, cream aim to provide our products at each and every
Contact address
PLOT NO. 52, INDUSTRIAL AREA, PHASE I CHANDIGARH-160002. (INDIA) Phone: +91 172-5072645, 5017792 (Sales) Fax: 0172-2641999

MDC PHARMACUETICALS PVT. LIMIT

Mobile: 09915500319 ( Export), 0981414112

E-Mail: Corporate: info@mdcpharmaceutical.c Export: export@mdcpharmaceutical.com

Hetero is a research based global pharmaceutical company focused on development, manufacturing and marketing of Active Pharmaceutical Ingredients (APIs), Intermediate Chemicals & Finished Dosages. Ever since its establishment in 1993, Hetero showed a tradition of excellence and deep sense of commitment in developing cost effective processes to offer wide range of affordable drugs. Hetero is building on the strengths of vertical integration in discovery research, process chemistry, API manufacturing, formulation development and

commercialization. Hetero is a leading international supplier with a rich portfolio of over 200 products from wide range of therapeutic categories both in active pharmaceutical ingredients and finished dosages.

Contact address
HETERO DRUGS LIMITED
7

7-2-A2, HETERO CORPORAT INDUSTRIALESTATES.SANATHNAGAR HYDERABAD 500 018. A.P. INDIA Tel: +914023704923/24/25/26/27/28 +91 40 23707171 / 7272 / 7744 Fax : +91 40 23714250 / 2370 4926 Email: contact@heterodrugs.com

Need to convert an active pharmaceutical ingredient into a suitable dosage form

Active pharmaceutical compounds (drugs) are used for the treatment of a disease or for prophylactic purpose. An Active Pharmaceutical Ingredient (API) may exist in solid, liquid or semisolid form. They are rarely prescribed to the patients as such i.e. without adding excipients, since the desired effect may not be obtained. Earlier, it was thought that excipients are inert in nature but, in recent time it is well known that excipients can greatly modify the intended effect of a drug. The API and excipients are suitably processed in pharmaceutical industry to convert them into dosage forms such as tablet, capsule, suspension, solution, etc. The selection of excipients and processing of drug excipients mixture is as important as API itself. Patient acceptability can be improved by controlling the organoleptic properties. Dosage form provides desired therapeutic level of a drug.

TABLET
INTRODUCTION :A tablet is a pharmaceutical solid unit dosage form of medicament or
7

medicaments. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted into a solid. The excipients can include Diluents, Binders or Granulating agents, Glidants (flow aids) and Lubricants to ensure efficient tabletting; disintegrates to promote tablet break-up in the digestive tract; sweeteners or flavors to enhance taste; and pigments to make the tablets visually attractive. A polymer coating is often applied to make the tablet smoother and easier to swallow, to control the release rate of the active ingredient, to make it more resistant to the environment (extending its shelf life), or to enhance the tablet's appearance. The compressed tablet is the most popular dosage form in use today.

Advantages and disadvantages of tablet as a dosage form

Advantages: I. Large scale manufacturing is feasible in comparison to other dosage forms. Therefore, economy can be achieved. II. Accuracy of dose is maintained since tablet is a solid unit dosage form. III.Tailor made release profile can be achieved. IV. Longer expiry period and minimum microbial spillage owing to lower moisture content.

V. As tablet is not a sterile dosage form, stringent environmental conditions are not required in the tablet department. VI. Ease of packaging (blister or strip) and easy handling over liquid dosage form.

VII. Easy to transport in bulk. Emergency supply supplies can be carried by patients. VIII. Organoleptic properties (taste, appearance and odour) are best improved by coating of tablet.
7

IX.

Product identification is easy and markings done with the help of grooved punches and printing with edible ink.

X. Different types of tablets are available like buccal, floating, colon targeting, effervescent, dispersible, soluble, and chewable, etc. XI. In composition to parenterals dosage form, a doctor or a nurse is not required for administration. I.e. self administration is possible.

XII. In comparison to capsules, tablets are more tamperproof. Disadvantages: I. It is difficult to convert a high dose poorly compressible API into a tablet of suitable size for human use. II. Difficult to formulate a drug with poor wettability, slow dissolution into a tablet. III. Slow onset of action as compared to parenterals, liquid orals and capsules. IV. The amount of liquid drug (e.g. Vitamin E, Simethicone) that can be trapped into a tablet is very less.

V. Difficult to swallow for kids, terminally ill and geriatric patients. VI. Patients undergoing radiotherapy cannot swallow tablet.

Essential Qualities of a Good Tablet:

I. II. III. IV.

They should be accurate and uniform in weight. The drugs should be uniformly distributed throughout the tablet. The size and shape should be reasonable for easy administration. The tablet should not be too hard that it may not disintegrate in the stomach. There should not be any compatibilities. They should be chemically and physically stable during storage.

V. VI.

VII.

They should not break during transportation crumble in the hands of the patient. They should be attractive in appearance. They must be able to release the medicinal agent(s) in the body in a predictable and reproducible manner. There should not be any manufacturing defects like cracking, chipping or discoloration. After administration it should disintegrate readily. They should be easy and economical in production.

VIII. IX.

X.

XI. XII.

Types of Tablet:
With advancement in technology and increase in awareness towards modification in standard tablet to achieve better acceptability as well as bioavailability, newer and more efficient tablet dosage forms are being developed. The main reasons behind formulation of different types of tablets are to create a delivery system that is relatively simple and inexpensive to manufacture, provide the dosage form that is convenient from patients perspective and utilize an approach that is unlikely to add complexity during regulatory approval process. To understand each dosage form, tablets here are classified by their route of administration and by the type of drug delivery system they represent within that route.

VARIOUS TYPES OF TABLETS: Tablet may be uncoated or coatedUncoated tablets are chewable tablet, effervescent tablet, lozenge tablet, soluble tablet, vaginal tablets(inserts) and sublingual tablet. Coated tablets are enteric
7

coated tablet, film coated tablet, implant, sugar coated tablet, and modifiedrelease tablet. A broken section of a coated tablet shows a core which is surrounded by a continuous layer of a different texture. The reasons for coating a tablet are: a) to protection of the active ingredients from air, moisture, light, b) to mask the unpleasant tastes and odor; and c) to improve appearance Chewable tabletThe tablet which is intended to be broken and chewed in between the teeth before ingestion. Antacid and vitamin tablets are usually prepared as chewable tablets. It is given to the children who have difficulty in swallowing and to the adults who dislike swallowing. Effervescent tabletThe tablet that contains acid substances and carbonate or hydrogen carbonate that react rapidly in the presence of water to release carbon dioxide. Sodium bicarbonate, citric acid and tartaric acid are added to the active ingredients to make the tablet effervescent. This preparation makes the tablet palatable. Lozenge tabletThe tablet that is intended to produce continuous effect on the mucous membrane of the throat. There is no disintegrating agent. The quality of the binding agent is increased so as to produce slow dissolution. Suitable sweetening (sugar), coloring and flavoring agents must be include in this formulation. Gum is used to give strength and cohesiveness to the lozenge and facilitating slow release of the active ingredient. Soluble tabletThe tablet that dissolves completely in liquid to produce solution of definite concentration. Mouth wash, gargle, skin lotion, douche; antibiotic, certain vitamins, and aspirin are given in this formulation. Sublingual tabletThe drug which is destroyed or inactivated within the gastrointestinal tract but can be absorbed through the mucosal tissue of the oral cavity is usually given in this formulation. The tablet is required to be placed below the tongue for the slow release of drug. But for immediate effect some medicaments are formulated in
7

such a way to dissolve within 1 to 2 minutes. Nitroglycerin is prepared in this formulation. Vaginal Tablets (Inserts)Sometimes vaginal suppositories or pessaries are prepared by compression which are known as vaginal tablets. Antibiotics and steroids are prepared in this way. Soluble additives are used for their preparation. They are generally ovoid or almond shaped for ease of insertion. Some laxative suppositories are also formulated as compressed tablets. The active medicaments are mixed with such disintegrating agents which either swell up after absorbing moisture or produce effervescence thus facilitating disintegration. These rectal tablets are covered with thin layers of polyethylene glycol which act as protective covering and also facilitate the insertion of these tablets into the rectum. Enteric coated tabletSome drugs are destroyed by gastric juice or causes irritation to the stomach. These two factors can be overcome by coating the tablet with cellulose acetate phthalate. This polymer is insoluble in gastric contents but readily dissolves in intestinal contents. So there is delay in the disintegration of dosage form until it reaches the small intestine. Like coated tablet, enteric coated tablet should be administered in whole form Broken or crushed form of the enteric coated tablet causes destruction of the drug by gastric juice or irritation to the stomach. Enteric coated tablet is comparatively expensive. Film coated tabletThe tablet that is covered with a thin layer or film of polymeric substance which protects the drug from atmospheric conditions and mask the objectionable taste and the odor of drug.

Implant` A small tablet that is prepared for insertion under the skin by giving a small surgical cut into the skin which is stitched after the insertion of the tablet. This tablet must be sterile one. The drug used in this preparation is usually water insoluble and the tablet provides a slow and continuous release of drug over

prolonged period of time ranging from 3 to 6 months or even more Contraceptive tablet is formulated as implant. Sugar coated tabletThe tablet that contains active ingredient(s) of unpleasant taste may be covered with sugar to make it more palatable. This type of tablet should be administered in whole form, otherwise the patient will experience the unpleasant taste of the active ingredient. Modified release tabletModified-released tablet is either uncoated or coated. This contains special additives or prepared by special procedure which, separately or together, is intended to modify the rate of release of the drug into the gastrointestinal tract. It prolongs the effect of drug and also reduces the frequency of administration of drug. Several drugs are available in modified release tablet such as indomethacin. There is another term popularly known as pill. Once the peoples idea was to use of pill in every ill. Now days the term has been only used in contraceptive preparations such as combination pill, Minipill, and morning after pill. Note: When two or more active pharmaceutical ingredients are needed to be administered simultaneously and they are incompatible, the best option for the formulation pharmacist would be to formulate multilayered tablet.

Excipients and their functionalities:

Excipient means any component other than the active pharmaceutical ingredient(s) intentionally added to the formulation of a dosage form. Many guidelines exist to aid in selection of non toxic excipients such as IIG (Inactive Ingredient Guide), GRAS (Generally Regarded As Safe), Handbook of Pharmaceutical Excipients and others. While selecting excipients for any formulation following things should be considered wherever possible: keep the excipients to a minimum in number minimize the quantity of each excipients and multifunctional excipients may be given preference over unifunctional excipients. Excipients play a crucial role in design of the delivery system, determining its quality and performance. Excipients though usually regarded as nontoxic there are examples of known excipient induced toxicities which include renal failure and death from diethylene glycol, osmotic diarrhoea caused by ingested mannitol,
7

hypersensitivity reactions from lanolin and cardiotoxicity induced by propylene glycol. Excipients are chosen in tablet formulation to perform a variety of functions likeI- For providing essential manufacturing technology functions (binders, glidants, lubricants may be added), II- For enhancing patient acceptance (flavors, colourants may be added), III- For providing aid in product identification (colourants may be added), IV- For Optimizing or modifying drug release (disintegrants, hydrophilic polymers, wetting agents, biodegradable polymers may be added), V- For enhancing stability (antioxidant, UV absorbers may be added)

Various excipients used in tablet formulation and their functionalities:

Diluents or Fillers: Diluents make the required bulk of the tablet when the drug dosage itself is inadequate to produce tablets of adequate weight and size. Binders or Granulating agents or Adhesives: Binders are added to tablet formulations to add cohesiveness to powders, thus providing the necessary bonding to form granules, which under compaction form a cohesive mass or a compact which is referred to as a tablet. Disintegrants: A disintegrant is added to most tablet formulations to facilitate a breakup or disintegration of the tablet when placed in an aqueous environment. Antifrictional Agents: Lubricants: Lubricants are intended to reduce the friction during tablet formation in a die and also during ejection from die cavity.
Antiadherents:

Antiadherents are added to reduce sticking or adhesion of any of the tablet granulation or powder to the faces of the punches or to the die wall.
Glidants-

Glidants are intended to promote the flow of tablet granulation or powder mixture from hopper to the die cavity by reducing friction between the particles. MISCELLANEOUS:
7

Wetting agents: Wetting Agents in tablet formulation aid water uptake and thereby enhancing disintegration and assisting in drug dissolution. Incorporation of anionic surfactant like Sodium Lauryl Sulphate (SLS) is known to enhance the dissolution.It has been established that SLS improves permeation of drug through biological membrane since it destroys the path through which drug has to pass and thus minimizing the path length for the drug to travel. Wetting agents are mainly added when hydrophobic drug is to be formulated into tablet. SLS, Sodium diisobutyl sulfosuccinate are used as wetting agent in tablet formulation. Dissolution retardants: Dissolution Retardants are incorporated into tablet formulation only when controlled release of drug is required. Waxy materials like stearic acid and their esters can be used as dissolution retardants. Dissolution enhancers: They are the agents that alter the molecular forces between ingredients to enhance the dissolution of solute in the solvent. Fructose, Povidone, Surfactants are used as dissolution enhancer. Adsorbents: Adsorbents are the agents that can retain large quantities of liquids. Therefore liquids like Vitamin E can be incorporated into tablets by addition of adsorbents. Most commonly used adsorbents in pharmaceuticals are anhydrous calcium phosphate, starch, magnesium carbonate, bentonite, kaolin, magnesium silicate, magnesium oxide and silicon dioxide. Generally the liquid to be adsorbed is first mixed with the adsorbent prior to incorporation into the formulation. Silicon dioxide when added can play as both glidant and an adsorbent role in the formula. Buffers: Buffers are added to maintain a required pH since a change in pH may cause significant alteration in stability. Most commonly used buffering agent in tablet formulation includes sodium bicarbonate, calcium carbonate, and sodium citrate Antioxidants: Antioxidants are added in tablet formulation to protect drug from undergoing oxidation. Antioxidants undergo oxidation in place of drug or they block the oxidation reaction or they act as synergists to other antioxidants. Chelators may also act as antioxidant. Most commonly used antioxidants include ascorbic acid and their esters , alpha-tocopherol , ethylene diamine tetra acetic acid , sodium
7

metabisulfite , sodium bisulfite , Butylated Hydroxy Toluene (BHT), Butylated Hydroxy Anisole (BHA) , citric acid , and tartaric acid . Chelating Agents: Chelating agents tend to form complexes with trace amount of heavy metal ions inactivating their catalytic activity in the oxidation of medicaments. Ethylenediamine tetracetic acid and its salts, Dihydroxy Ethyl Glycine, Citric Acid and Tartaric Acid are most commonly used chelators. Preservatives: Preservatives may be a part of tablet formulation in order to prevent the growth of microorganisms in tablet formulation. Parabens like methyl, propyl, benzyl, butyl p-hydroxy benzoate are used as preservatives. Colourants: Colourants neither contribute to therapeutic activity nor do they improve product bioavailability or stability but are incorporated into tablets for purposes like to facilitate identification of similar looking products with in a product line to avoid mix ups, to facilitate identification of products of similar appearance that exist in the lines of different manufacturers, to overcome colour change on aging, disguising of off-colour drugs, for brand image in the market, to enhance the aesthetic appearance of the product to have better patient acceptance. Most widely used colourants are dyes and lakes which are FD & C and D & C approved. Dyes are generally applied as solution especially in the granulating agent. Lakes are usually employed as dry powders for colouring. In general, direct compression tablets are coloured with lakes because no granulation step is used. Natural colourants can be used and generally they do not require the FDA certification before use in drug products. One of the important advantage in using lakes is reduced risk of interaction between the drug and other ingredients as well as colour development is rapid which reduces processing time .While employing wet granulation , care should be taken to prevent colour migration during drying . In any coloured tablet, the formulation should be checked for resistance to colour changes on exposure to light. Reflectance Spectrophotometry, Tristimulus Colourimetric Measurements and Microreflectance Photometer used to measure the colour uniformity and gloss on a tablet surface. Some commonly used colorants- Erythrosine, Allura red AC, Tartrazine, Indigotine, Fast Green, Brilliant Blue etc.

Flavours: Flavours are commonly used to improve the taste of chewable tablets as well as mouth dissolved tablets. Flavours are incorporated either as solids (spray dried flavours) or oils or aqueous (water soluble) flavours. Solids that is dry flavours are easier to handle and generally more stable than oils. Oil is usually added at the lubrication step because of its sensitivity to moisture and their tendency to volatilize when heated during drying. It may also be adsorbed onto an excipient and added during the lubrication process. The maximum amount of oil that can be added to granulation without affecting tableting characteristics is 0.5 to 0.75 %w/w. aqueous flavours are less used because of its instability on aging. Sweeteners: Sweeteners are added to tablet formulation to improve the taste of chewable tablets. Some commonly used sweeteners are Mannitol, Lactose, Sucrose, Dextrose, Saccharin, Cyclamate, Aspartame. Saccharin is 500 times sweeter than sucrose. Its major disadvantages are that it has a bitter aftertaste and is carcinogenic. Even cyclamate is carcinogenic. Aspartame is about 180 times sweeter than sucrose. The primary disadvantage of aspartame is its lack of stability in the presence of moisture. When aspartame is used with hygroscopic components, it will be necessary to determine its stability under conditions in which the product can adsorb atmospheric moisture. Aspartame is available in market under the brand Nutrasweet manufactured and marketed by Nutrasweet Company.

Operations Involved in Tablet Manufacturing

7

The manufacture of oral solid dosage forms such as tablets is a complex multistage process under which the starting materials change their physical characteristics a number of times before the final dosage form is produced. Traditionally, tablets have been made by granulation, a process that imparts two primary requisites to formulate: compactibility and fluidity. Both wet granulation and dry granulation (slugging and roll compaction) are used. Regardless of weather tablets are made by direct compression or granulation, the first step, milling and mixing, is the same; subsequent step differ. Numerous unit processes are involved in making tablets, including particle size reduction and sizing, blending, granulation, drying, compaction, and (frequently) coating. Various factors associated with these processes can seriously affect content uniformity, bioavailability, or stability.

Various unit operation sequences in tablet manufacturing

Typical manufacturing process of tablets

TABLE- TYPICAL UNIT OPERATION INVOLVED IN WET GRANULATION, DRY GRANULATION AND DIRECT COMPRESSION

WET GRANULATION

DRY GRANULATION

DIRECT COMPRESSION

1. Milling and mixing of drugs and excipients 2. Preparation of binder solution 3. Wet massing by addition of binder solution or granulating solvent

1. Milling and mixing of drugs and excipients 2. Compression into slugs or roll compaction 3. Milling and screening of slugs and compacted powder

1. Milling and mixing of drugs and excipients 2. Compression of tablet

4. Screening of wet mass 4. Mixing with lubricant and disintegrant 5. Drying of the wet 5. Compression of tablet granules 6. Screening of dry granules 7. Blending with lubricant and disintegrant to produce 8. Compression of tablet

Dispensing:
(Weighing and Measuring) Dispensing is the first step in any pharmaceutical manufacturing process. Dispensing is one of the most critical steps in pharmaceutical manufacturing; as during this step, the weight of each ingredient in the mixture is determined according to dose. Dispensing may be done by purely manual by hand scooping from primary containers and weighing each ingredient by hand on a weigh scale, manual weighing with material lifting assistance like Vacuum transfer and Bag lifters, manual or assisted transfer with automated weighing on weigh table, manual or assisted filling of loss-in weight dispensing system, automated dispensaries with mechanical devices such as vacuum loading system and screw feed system. Issues like weighing accuracy, dust control (laminar air flow booths, glove boxes), during manual handling, lot control of each ingredient,

material movement into and out of dispensary should be considered during dispensing.

Sizing:
The sizing (size reduction, milling, crushing, grinding, pulverization) is an impotent step (unit operation) involved in the tablet manufacturing. In manufacturing of compressed tablet, the mixing or blending of several solid ingredients of pharmaceuticals is easier and more uniform if the ingredients are approximately of same size. This provides a greater uniformity of dose. A fine particle size is essential in case of lubricant mixing with granules for its proper function. Advantages associated with size reduction in tablet manufacture are as follows: i) It increases surface area, which may enhance an actives dissolution rate and hence bioavailability. ii) Improved the tablet-to-tablet content uniformity by virtue of the increased number of particles per unit weight. iii) Controlled particle size distribution of dry granulation or mix to promote better flow of mixture in tablet machine. iv) Improved flow properties of raw materials. v) Improved colour and/or active ingredient dispersion in tablet excipients. vi) Uniformly sized wet granulation to promote uniform drying

There are also certain disadvantages associated with this unit operation if not controlled properly. They are as follows: i) A possible change in polymorphic form of the active ingredient, rendering it less or totally inactive, or unstable. ii) A decrease in bulk density of active compound and/or excipients, which may cause flow problem and segregation in the mix. iii) An increase in surface area from size reduction may promote the adsorption of air, which may inhibit wettability of the drug to the extent that it becomes the limiting factor in dissolution rate. A number of different types of machine may be used for the dry sizing or milling process depending on whether gentle screening or particle milling is needed. The
7

ranges of equipment employed for this process includes Fluid energy mill, Colloidal mill, Ball mill, Hammer mill, Cutting mill, Roller mill, Conical mill, etc.

Powder blending:
The successful mixing of powder is acknowledged to be more difficult unit operation because, unlike the situation with liquid, perfect homogeneity is practically unattainable. In practice, problems also arise because of the inherent cohesiveness and resistance to movement between the individual particles. The process is further complicated in many system, by the presence of substantial segregation influencing the powder mix. They arise because of difference in size, shape, and density of the component particles. The powder/granules blending are involved at stage of pre granulation and/or post granulation stage of tablet manufacturing. Each process of mixing has optimum mixing time and so prolonged mixing may result in an undesired product. So, the optimum mixing time and mixing speed are to be evaluated. Blending step prior to compression is normally achieved in a simple tumble blender. The Blender may be a fixed blender into which the powders are charged, blended and discharged. It is now common to use a bin blender which blends.

Commonly used Blenders are as follows:

Double Cone Blender: The Double Cone Blender is an efficient and versatile machine for mixing dry powder and granulates uniformly. Two-thirds of the volume of the cone blender is filled to ensure proper mixing. Double Cone Blender is used for pharmaceutical, food, chemical and cosmetic products, etc. These machines are extensively used in the pharmaceutical industry to granulate and blend medicated powders. It is also the best way to mix very heavy and abrasive products for total discharge of product with minimal retention. Blender features multi shear deflector plates for the improved blending efficiency of free flowing powders and granules. Salient Features: The conical shape at both ends enables uniform mixing and easy discharge.

The cone is statically balanced to avoid any excessive load on the gear box and motor. While the powder can be loaded into the cone through a wider opening, it can be discharged-through a mucon valve or a slide valve. Depending upon the product, paddle-type battles can be provided on the shaft for better mixing. Maximum care has been taken ensure safe operation of the unit. It can also be operated through a timer. The contact parts are made of either S.S. 304 or 316 L. Flame-proof motor can be supplied as option.

Octagonal Blender with Cylindrical Container: The Octagonal Blender is an efficient and versatile blending machine for mixing and lubrication process of dry granules equally. It can be used for pharmaceutical, food, chemical and cosmetic products etc. Octagonal Blender consists of octagon shaped body, rectangular central portion and top and bottom polygonal frustum. It is provided with baffles for fast and efficient mixing, charging port and outlet with butterfly valve. It is very useful machinery for pharmaceutical industry where in gentle blending of dry granules or powder is to be done. Other important feature of this machine is easy to clean in place. The bin charging system can also be incorporated in it which is a dust free closed system for charging and discharging of powders or granules. The powder consumption is comparatively lower than the other similar type of blender. Two third of the volume of the cone blender is filled to ensure proper mixing. The Octagonal blender gives best result for granules due to very slow speed and octagon shape of container. In Octagonal blender the granules from all sides due to the octagonal shape of the product container, hence requirement of RPM is less. Suitable mainly for Crystalline & Granular type material. This type of material gets sufficient continuous movement due to their shape if container has only slow movement and will results in good quality of blending / lubrication of granules.

V-Type Blenders: V Blender is highly favored by the pharmaceutical and fine chemical industries. As the vessel rotates from the "V" position, the batch is divided into right and left legs. As the vessel continues its rotation, the batch blends and recombines. V Blenders can be built to suit customer requirements. The Blender is most suitable for paints, dye-stuffs and pharmaceutical. Suitable for dry mixing of products in powder form. Special Features:

Suitable for dry mixing of products in powder form. Easy for loading and unloading. Easy for cleaning. All contact parts are made out of SS304 / SS316 or SS316 L quality material, as per customer requirement. Simple design requires minimum maintenance. General structure & safety guards made out of mild steel & painted in Standard Model and made out of SS304 & polished to the matt finish in GMP Model. The "V" shape gives sufficient contineous movement to the granules, result in good quality. Maximum care has been taken to ensure safe operation of the unit. Manual rotating facility with hand wheel for inching.

Granulation:

Granulation may be defined as a size enlargement process which converts small particles into physically stronger & larger agglomerates. Granulation method can be broadly classified into three types: Wet granulation, Dry granulation, and Dry Granulation incorporating bound moisture . Ideal characteristics of granules:The ideal characteristics of granules include uniformity, good flow, and compactibility. These are usually accomplished through creation of increased density, spherical shape, narrow particle size distribution with sufficient fines to fill void spaces between granules, adequate moisture (between 1-2%), and incorporation of binder, if necessary. The effectiveness of granulation depends on the following properties i) Particle size of the drug and excipients ii) Type of binder (strong or weak) iii) Volume of binder (less or more) iv) Wet massing time ( less or more) v) Amount of shear applied to distribute drug, binder and moisture. vi) Drying rate ( Hydrate formation and polymorphism) Why Granulation.? Granulation is carried out for various reasons, one of those is to prevent the segregation of the constituents of powder mix. Segregation is due to differences in the size or density of the component of the mix. Normally, the smaller and/or denser particles tend to concentrate at the base of the container with the larger and/or less dense ones on the top. An ideal granulation will contain all the constituents of the mix in the correct proportion in each granule and segregation of granules will not occur. Many powders, because of their small size, irregular shape or surface characteristics, are cohesive and do not flow well. Granules produced from such a cohesive system will be larger and more isodiametric, both factors contributing to improved flow properties. Some powders are difficult to compact
7

even if a readily compactable adhesive is included in the mix, but granules of the same powders are often more easily compacted. This is associated with the distribution of the adhesive within the granule and is a function of the method employed to produce the granule. For example, if one were to make tablets from granulated sugar versus powdered sugar, powdered sugar would be difficult to compress into a tablet and granulated sugar would be easy to compress. Powdered sugars small particles have poor flow and compression characteristics.

Drying:
Drying is a most important step in the formulation and development of pharmaceutical product. It is important to keep the residual moisture low enough to prevent product deterioration and ensure free flowing properties. The commonly used dryer includes Fluidized bed dryer, Vacuum tray dryer, Microwave dryer, Spray dryer, Freeze dryer, Turbo - tray dryer, Pan dryer, etc.

Tablet compression:
After the preparation of granules (in case of wet granulation) or sized slugs (in case of dry granulation) or mixing of ingredients (in case of direct compression), they are compressed to get final product. The compression is done either by single punch machine (stamping press) or by multi station machine (rotary press). The tablet press is a high-speed mechanical device. It 'squeezes' the ingredients into the required tablet shape with extreme precision. It can make the tablet in many shapes, although they are usually round or oval. Also, it can press the name of the manufacturer or the product into the top of the tablet. Each tablet is made by pressing the granules inside a die, made up of hardened steel. The die is a disc shape with a hole cut through its centre. The powder is compressed in the centre of the die by two hardened steel punches that fit into the top and bottom of the die. The punches and dies are fixed to a turret that spins round. As it spins, the punches are driven together by two fixed cams - an upper cam and lower cam.

The top of the upper punch (the punch head) sits on the upper cam edge .The bottom of the lower punch sits on the lower cam edge. The shapes of the two cams determine the sequence of movements of the two punches. This sequence is repeated over and over because the turret is spinning round. The force exerted on the ingredients in the dies is very carefully controlled. This ensures that each tablet is perfectly formed. Because of the high speeds, they need very sophisticated lubrication systems. The lubricating oil is recycled and filtered to ensure a continuous supply.

STAGE OCCURRING DURING COMPRESSION

Stage 1: Top punch is withdrawn from the die by the upper cam Bottom punch is low in the die so powder falls in through the hole and fills the die. Stage 2: Bottom punch moves up to adjust the powder weight-it raises and expels some powder
7

Stage 3: Top punch is driven into the die by upper cam Bottom punch is raised by lower cam. Both punch heads pass between heavy rollers to compress the powder. Stage 4: Top punch is withdraw by the upper cam.Lower punch is pushed up and expels the tablet. Tablet is removed from the die surface by surface plate Stage 5: Return to stage 1

Auxiliary Equipments:
(1) Granulation Feeding Device: In many cases, speed of die table is such that the time of die under feed frame is too short to allow adequate or consistent gravity filling of die with granules, resulting in weight variation and content uniformity. These also seen with poorly flowing granules. To avoid these problems, mechanized feeder can employ to force granules into die cavity. (2)Tablet weight monitoring devices: High rate of tablet output with modern press requires continuous tablet weight monitoring with electronic monitoring devices like Thomas Tablet Sentinel, Pharmakontroll and Killan control System-MC. They monitors force at each compression station by starin gage technology which is then correlated with tablet weight. (3)Tablet Deduster: In almost all cases, tablets coming out of a tablet machine bear excess powder on its surface and are run through the tablet deduster to remove that excess powder. (4)Fette machine: Fette machine is device that chills the compression components to allow the compression of low melting point substance such as waxes and thereby making it possible to compress product with low meting points.

Packaging:
Pharmaceutical manufacturers have to pack their medicines before they can be
7

sent out for distribution. The type of packaging will depend on the formulation of the medicine.'Blister packs' are a common form of packaging used for a wide variety of products. They are safe and easy to use and they allow the consumer to see the contents without opening the pack. Many pharmaceutical companies use a standard size of blister pack. This saves the cost of different tools and to change the production machinery between products. Sometimes the pack may be perforated so that individual tablets can be detached. This means that the expiry date and the name of the product have to be printed on each part of the package. The blister pack itself must remain absolutely flat as it travels through the packaging processes, especially when it is inserted into a carton. This poses interesting problems for the designers. Extra ribs are added to the blister pack to improve its stiffness.

Manufacturing methods/Direct compression:

In early days, most of the tablets require granulation of the powdered Active Pharmaceutical Ingredient (API) and Excipients. At the availability of new excipients or modified form of old excipients and the invention of new tablet machinery or modification of old tablet machinery provides an ease in manufacturing of tablets by simple procedure of direct compression. Amongst the techniques used to prepare tablets, direct compression is the most advanced technology. It involves only Blending and Compression. Thus offering advantage particularly in terms of speedy production. Because it requires fewer unit operations, less machinery, reduced number of personnel and considerably less processing time along with increased product stability. Definition: The term Direct compression is defined as the process by which tablets are compressed directly from powder mixture of API and suitable excipients. No pretreatment of the powder blend by wet or dry granulation procedure is required. The events that motivates the industry people to use direct compression technique I. Commercial availability of the directly compressible excipients possessing both good compressibility and good flowability. For example: Spray dried lactose, Anhydrous lactose, Starch-1500, microcrystalline cellulose, Sorbitol
7

II. Major advances in tablet compression machinery, i) Improved positive die feeding ii) Precompression of powder blend

Merits:
i) Direct compression is more efficient and economical process as compared to other processes, because it involves only dry blending and compaction of API and necessary excipients. ii) The most important advantage of direct compression is economical process.Reduced processing time, reduced labor costs, fewer manufacturing steps, and less number of equipments are required, less process validation, reduced consumption of power. iii) Elimination of heat and moisture, thus increasing not only the stability but also the suitability of the process for thermolabile and moisture sensitive APIs. iv)Particle size uniformity. v) Prime particle dissolution. vi)The chances of batch-to-batch variation are negligible, because the unit operations required for manufacturing processes is fewer. vii) Chemical stability problems for API and excipient would be avoided. viii) Provides stability against the effect of aging which affects the dissolution rates. Merits over wet granulation process: The variables faced in the processing of the granules can lead to significant tableting problems. Properties of granules formed can be affected by viscosity of granulating solution, the rate of addition of granulating solution, type of mixer used and duration of mixing, method and rate of dry and wet blending. The above variables can change the density and the particle size of the resulting granules and may have a major influence on fill weight and compaction qualities. Drying can lead to unblending as soluble API migrates to the surface of the drying granules.

Demerits:
Excipient Related: i) Problems in the uniform distribution of low dose drugs. ii) High dose drugs having high bulk volume, poor compressibility and poor flowability are not suitable for direct compression. For example, Aluminium
7

Hydroxide, Magnesium Hydroxide iii) The choice of excipients for direct compression is extremely critical. Direct compression diluents and binders must possess both good compressibility and good flowability. iv) Many active ingredients are not compressible either in crystalline or amorphous forms. v) Direct compression blends may lead to unblending because of difference in particle size or density of drug and excipients. Similarly the lack of moisture may give rise to static charges, which may lead to unblending. vi) Non-uniform distribution of colour, especially in tablets of deep colours.

Process Related: i) Capping, lamination, splitting, or layering of tablets is sometimes related to air entrapment during direct compression. When air is trapped, the resulting tablets expand when the pressure of tablet is released, resulting in splits or layers in the tablet. ii) In some cases require greater sophistication in blending and compression equipments. iii) Direct compression equipments are expensive.

Manufacturing steps for direct compression:

Direct compression involves comparatively few steps: i) Milling of drug and excipients. ii) Mixing of drug and excipients. iii) Tablet compression.

Direct compression Excipients: Direct compression excipients mainly include diluents, binders and disintegrants. Generally these are common materials that have been modified during the chemical manufacturing process, in such a way to improve compressibility and flowability of the material. The physicochemical properties of the ingredients
7

such as particle size, flowability and moisture are critical in direct compression tableting. The success of direct compression formulation is highly dependent on functional behavior of excipients.

An ideal direct compression excipient should possess the following attributes: i) It should have good compressibility. ii) It should possess good hardness after compression, that is material should not possess any deformational properties; otherwise this may lead to capping and lamination of tablets. iii) It should have good flowability. iv) It should be physiologically inert. v) It should be compatible with wide range of API. vi) It should be stable to various environmental conditions (air, moisture, heat, etc.). vii) It should not show any physical or chemical change in its properties on aging. viii) It should have high dilution potential. i.e. Able to incorporate high amount of API. ix) It should be colourless, odorless and tasteless. x) It should accept colourants uniformity. xi) It should possess suitable organoleptic properties according to formulation type, that is in case of chewable tablet diluent should have suitable taste and flavor.e.g mannitol produces cooling sensation in mouth and also sweet test. xii) It should not interfere with bioavailability and biological activity of active ingredients. xiii) It should be easily available and economical in cost.

Major excipients required in direct compression

I. Diluents II .Binders III .Disintegrants Diluents: Selection of direct compression diluent is extremely critical, because the success
7

or failure of direct compression formulation completely depends on characteristics of diluents. There are number of factors playing key role in selection of optimum diluent. Factors like- Primary properties of API (particle size and shape, bulk density, solubility), the characteristics needed for processing (flowability, compressibity), and factors affecting stability (moisture, light, and other environmental factors), economical approach and availability of material. After all, one can say that raw material specifications should be framed in such a way that they provide an ease in manufacturing procedures and reduce chances of batch to batch variation. Binders: Binders are the agents used to impart cohesive qualities to the powdered material. The quality of binder used has considerable influence on the characteristic of the direct compression tablets. The direct compression method for preparing tablets requires materials which are not only free flowing but also sufficiently cohesive to act as binder. Disintegrants: A disintegrant is added to most tablet formulations to facilitate a breakup or disintegration of the tablet when placed in an aqueous environment

Manufacturing methods/Granulation
Granulation may be defined as a size enlargement process which converts small particles into physically stronger & larger agglomerates.

Granulation techniques:
In pharmaceutical industry, two types of granulation technologies are employed, namely, Wet Granulation and Dry Granulation. Wet granulation: Wet granulation, the process of adding a liquid solution to powders, is one of the most common ways to granulate. It involves the massing of a mix of dry primary powder particles using a granulating fluid. The fluid contains a solvent which must be volatile so that it can be removed by drying, and be non-toxic. Typical liquids include water, ethanol and isopropanol either alone or in combination.
7

The liquid solution can be either aqueous based or solvent based. Aqueous solutions have the advantage of being safer to deal with than solvents. Procedure: Step 1: The active ingredient and excipients are weighed and mixed. Step 2: The wet granulate is prepared by adding the liquid binderadhesive to the powder blend and mixing thoroughly. Examples of binders/adhesives include aqueous preparations of cornstarch, natural gums such as acacia, cellulose derivatives such as methyl cellulose, gelatin, and povidone. Step 3: Screening the damp mass through a mesh to form pellets or granules. Step 4: Drying the granulation. A conventional tray-dryer or fluid-bed dryer are most commonly used. Step 5: After the granules are dried, they are passed through a screen of smaller size than the one used for the wet mass to create granules of uniform size.

Limitation of wet granulation:

i) The greatest disadvantage of wet granulation is its cost. It is an expensive process because of labor, time, equipment, energy and space requirements. ii) Loss of material during various stages of processing iii) Stability may be major concern for moisture sensitive or thermo labile drugs iv) Multiple processing steps add complexity and make validation and control

Special wet granulation techniques:

i) High shear mixture granulation ii) Fluid bed granulation iii) Extrusion-spheronization iv) Spray drying

High shear mixture granulation:

High shear mixture has been widely used in Pharmaceutical industries for blending and granulation. Blending and wet massing is accompanied by high mechanical agitation by an impeller and a chopper. Mixing, densification and agglomeration are achieved through shear and compaction force exerted by the impeller.
7

Advantages: i) Short processing time ii) Less amount of liquid binders required compared with fluid bed. iii) Highly cohesive material can be granulated.

Fluid bed granulation: Fluidization is the operation by which fine solids are
transformed into a fluid like state through contact with a gas. At certain gas velocity the fluid will support the particles giving them free mobility without entrapment. Fluid bed granulation is a process by which granules are produced in a single equipment by spraying a binder solution onto a fluidized powder bed. The material processed by fluid bed granulation are finer, free flowing and homogeneous.

Extrusion and Spheronization: It is a multiple step

process capable of making uniform sized spherical particles. It is primarily used as a method to produce multi-particulates for controlled release application. Advantages: i) Ability to incorporate higher levels of active components without producing excessively larger particles. ii) Applicable to both immediate and controlled release dosage form.

Spray drying granulation: It is a unique granulation technique that directly

converts liquids into dry powder in a single step. This method removes moisture instantly and converts pumpable liquids into a dry powder. Advantages: i) Rapid process ii) Ability to be operated continuously iii) Suitable for heat sensitive product

Lists of equipments for wet granulation:

High Shear granulation: i) Little ford Lodgie granulator ii) Little ford MGT granulator iii) Diosna granulator iv) Gral mixer Granulator with drying facility: i) Fluidized bed granulator ii) Day nauta mixer processor iii) Double cone or twin shell processor iv) Topo granulator Special granulator: i) Roto granulator ii) Marumerizer

Dry granulation:
The dry granulation process is used to form granules without using a liquid solution because the product to be granulated may be sensitive to moisture and heat. Forming granules without moisture requires compacting and densifying the powders. In this process the primary powder particles are aggregated under high pressure. Dry granulation can be conducted under two processes; either a large tablet (slug) is produced in a heavy duty tabletting press or the powder is squeezed between two rollers to produce a sheet of materials (roller compactor, commonly referred to as a chilsonator).

Advantages:
The main advantages of dry granulation or slugging are that it uses less equipments and space. It eliminates the need for binder solution, heavy mixing equipment and the costly and time consuming drying step required for wet granulation. Slugging can be used for advantages in the following situations: i) For moisture sensitive material ii) For heat sensitive material iii) For improved disintegration since powder particles are not bonded together by a binder

Disadvantages:
i) It requires a specialized heavy duty tablet press to form slug. ii) It does not permit uniform colour distribution as can be. iii) Achieved with wet granulation where the dye can be incorporated into binder liquid. iv) The process tends to create more dust than wet granulation, increasing the potential contamination.

Steps in dry granulation:

i) Milling of drugs and excipients ii) Mixing of milled powders iii) Compression into large, hard tablets to make slug iv) Screening of slugs v) Mixing with lubricant and disintegrating agent vi) Tablet compression

Two main dry granulation processes:

Slugging process:
Granulation by slugging is the process of compressing dry powder of tablet formulation with tablet press having die cavity large enough in diameter to fill quickly. The accuracy or condition of slug is not too important. Only sufficient pressure to compact the powder into uniform slugs should be used. Once slugs are produced they are reduced to appropriate granule size for final compression by screening and milling. Factors which determine how well a material may slug:i) Compressibility or cohesiveness of the mater ii) Compression ratio of powder iii) Density of the powder iv) Machine type v) Punch and die size vi) Slug thickness vii) Speed of compression viii) Pressure used to produce slug
7

Roller compaction: The compaction of powder by means of pressure roll can

also be accomplished by a machine called chilsonator. Unlike tablet machine, the chilsonator turns out a compacted mass in a steady continuous flow. The powder is fed down between the rollers from the hopper which contains a spiral auger to feed the powder into the compaction zone. Like slugs, the aggregates are screened or milled for production into granules.

Formulation for dry granulation

The excipients used for dry granulation are basically same as that of wet granulation or that of direct compression. With dry granulation it is often possible to compact the active ingredient with a minor addition of lubricant and disintegrating agent. Fillers that are used in dry granulation include the following examples: Lactose, dextrose, sucrose, MCC, calcium sulphate, etc.

SIEVING:
A sieve or screener is an essential part of every pharmaceutical production process, particularly as product quality and integrity are so important. The use of a sieve gets rid of oversized contamination to ensure that ingredients and finished products are quality assured during production and before use or despatch. In basic terms, a sieve consists of a housing containing a removable wire mesh of a defined aperture size. This assembly is vibrated by an electric motor so that small particles can pass through the mesh apertures and any particles or contamination that are too big remain on the top. Most units used in the pharmaceutical industry tend to be circular and of a high-quality good manufacturing practice (GMP) design by ensuring accurate separation Stainless steel mesh with a high tolerance on the apertures is also specified to give excellent product quality.

Types of Sieving:
There are two main types of sieving safety screening and grading. Safety screening, sometimes known as control sieving or security/check screening of powders, is done to ensure the correct product quality of powders. Basically, the sieve removes any oversized contamination from the powder, which could be something that has accidentally found its way into the process line (e.g. some packaging, a piece of personal protective equipment or extraneous particles that may be inherent in the material). Removal of this contamination improves the quality of the powder and final product and, therefore, safeguards the pharmaceutical company's reputation. Grading or sizing of powders or granules is done to separate different ranges of particle sizes. For example, primary and intermediates must be sieved to remove oversize and undersize particles to ensure a correct particle size distribution ready for granulation and subsequent tablet pressing.

Rapid Mixer Granulator:

Rapid mixer granulator is a high precision machine used for dry mixing and wet granulation of raw material/ingredients in the same container. The machine mixes the dry components first, followed by wet granulation without transferring the dry mixture. It is suitable for fast, efficient and uniform mixing or granulation of raw material. The impeller sets the raw material mixture in motion ensuring uniform mixing of dry material followed by uniform wetting of granules; the mix is finally ejected through an outlet. The capacity of this pharmaceutical equipment varies and can range from 25 ltrs to 1000 ltrs. Benefits Using Rapid mixer granulator, we obtain: 1- Fluidity and compressibility in powders 2- Mechanical properties that exists in pills 3- Bio-disponibility 4- Homogeneity in mixture in low actives doses 5- Homogeneity in final output or product Application of Rapid Mixer Granulator
1- Pharmaceutical 2- Chemical 7

3- Cosmetic 4- Food

Spray Granulators:
Spray granulators are widely used in pharmaceutical industry for rapidly drying suspensions, solutions and viscous materials into free-flowing granules. These machines have a very high efficiency of drying and can evaporate considerable amount of fluids and liquids from particles, helping to save energy, process time. Compared with other granulation processes, spray granulation has major advantages to offer in terms of the quality of the final product.

Working of Spray Granulator: The process involves mixing of dry ingredients, adding liquid to the mixture and granulating them; this is followed by the drying of the granules. Spray granulators agglomerate fine particles into large and free flowing granules; granulation occurs by spraying liquid into fluidized powder. Purpose of Spray Granulation Process: The purpose of spray granulation is to generate particles with a defined structure, shape, size and composition according to specification.

Uses:
Spray granulator is used for:

Dispersion activities Agglomeration Hot melt coating Spray drying

Application of Spray Granulator:

Phamaceutical industry: Tablet, capsule, low sugar or no sugar granule of medicines. Foodstuff: Coffee, cocoa, milk powder, juice of granulate, flavoring . Other industries: Feed chemical fertilizer, peticide, pigment, dyestuff and so on.

DRYING OF WET GRANULESDrying id defined as the removal of small amounts of water or other liquid from a material by the application of heat. Types of dryers:1. 2. 3. 4.

Static Bed Dryer:- Tray dryer & freeze dryer Moving bed dryer:- Drum dryer Fluidised bed dryer:- Fluidised bed dryer Pneumatic dryer:- Spray dryer

Various types of dryers are usedTRAY DRYERIn tray dryer, hot air is continuously circulated. Forced convection heating takes place to remove moisture from the solids placed on trays. Simultaneously, the moist air is removed partially. SPECIAL FEATURES:

Electrical / Steam / Oil Heating mode. Inside surface is painted with heat resistant aluminum paint and out side with synthetic enamel.

TECHNICAL SPECIFICATIONS:
7

Tray Size : 16" x 32" x 1.25" All required electrical switch gears are of L&T / Siemens / BCHL make. Tray material : Aluminum/SS304/SS316 Fan motor: 0.5 / 1.0 / 1.0 / 2.0 h.p. No. of Fan: 1 No. / 1 No. / 2 Nos / 4 Nos. Temp. Range: up to 100 degree C.

Multi Mill
SALIENT FEATURES:

Suitable for dry and wet granules. All contact parts are made out of SS304/SS316 quality material. All contact parts can be easily and quickly dismantled and cleaned. Castores provided for the ease of mobility. Sieves available in sizes of 0.5 to 12 mm hole dia. 12 nos. beaters with knife edges, impact edges & 02 nos. scrapper blades

TECHNICAL SPECIFICATIONS:

Drive motor: 3 HP / 1440 rpm D.O.L. starter provided with reversible switch. Rotor RPM: 750 / 1400 / 2200 / 2800 Output: 25 to 175 kgs. / Hr.

Fluid Bed Dryer

In fluidised bed dryer, hot air (gas) is passed at high pressure through a perforated bottom of the container containing granules to be dried. The granules are lifted from the bottom and suspended in the stream of air. This condition is called fluidised state. The hot air is surrounding every granule to completely dry them. Thus materials or granules are uniformly dried.

Tablet compression :SALIENT FEATURES:

Models available in 10, 30, 60,100,150, 200,250 Kgs. Capacities (Batch size). Uniformity in drying and reduction in drying time. Micro filter to prevent any fine dust to pass through the products with inlet air. An explosion safety flap of adequate capacity at the rear of dryer and an earthing point to prevent static charge in the machine. Timer provided to set process time. Temperature indicator cum controller for inlet and outlet air temperature.(In Electrically Heated Model only) Can be used in the fields of Pharmaceuticals, Bulk Drugs, Dyes & Chemicals, Food Products & Starch Derivatives, Pesticides, Phyto Chemicals, and Catalysts etc.

For the compression of granules in the form of tablet various types of machines are used which are known as tablet making machines or tablet presses. Various types of machines so used are as follows

1. Single punch machine 2.Multi punch machines 3. Rotary tablet machine

7

4. High speed rotary tablet machine 5. Multilayer rotary tablet machine. Single punch machine:
Single Punch Tablet Press Machine
Specification Stroke per minute Max. Dia. of Tablet Depth of fills Pressure Light Duty 45 Heavy Duty ----

25 mm 19 mm 10 Tons

50 mm 25 mm 12 Tons 2 HP, 3 HP

Power Required 2 HP, 1.5 HP Height of Machine Net Weight Capacity 300 kgs.

500 kgs.

1 gm to 4 gm depend upon Diameter of Tablet 1 - 20 gm

Rotary tablet machine:Single Rotary Tablet is a fully automated machine. For large scale production, rotary tablet machines are used. The high speed rotary tablet machines are fitted with as 70 sets of dies and punches and can produce up to 10000 tablets/min. Applications of Single Rotary Tablet Press :7

Mini Tablet Press is used in pharmaceutical industry, pharmacy colleges, formulation and development laboratories in pharmaceutical companies and research institutions to produce all type of round tablets, ball shaped tablets, irregular tablets and tablets of engraved on one side and on both side.

Multilayer rotary tablet machine:-

With multilayer rotary tablet machines, tablets having one, two or three layers can be produced. They have the advantage that in compatible drugs can be compressed in different layers and separating these layers with an inert material. Sustained action preparations can also be prepared by this method. Key features of the Multilayer Tablet Press are as follows: I. II. III. IV. V. VI. VII. Variable frequency drive for speed control Pre-compression to improve compressibility and quality of tablet Adjustable upper punch penetration Force feeding systems to maintain the uniform filling and precise weight Common drive for three force feeders Zero clearance force feeder, Efficient dust extraction system to avoid layer mixing Overload pressure release and sampling mechanism through hydraulics

Tablet coating:Coated tablets are defined as tablets covered with one or more layers of mixture of various substances such as natural or synthetic resins ,gums ,inactive and insoluble filler, sugar, plasticizer, polyhydric alcohol ,waxes ,authorized colouring material and some times flavoring material . Coating may also contain active ingredient. Substances used for coating are usually applied as solution or suspension under conditions where vehicle evaporates. Aspects of tablet coating:7

I. Therapy i) Avoid irritation of oesophagus and stomach ii) Avoid bad taste iii) Avoid inactivation of drug in the stomach iv) Improve drug effectiveness v) Prolong dosing interval vi) Improve dosing interval vii) Improve patient compliance II. Technology i) Reduce influence of moisture ii) Avoid dust formation iii) Reduce influence of atmosphere iv) Improve drug stability v) Prolong shelf life

Basic principle of tablet coating:The principle of tablet coating is relatively simple. Tablet coating is the of coating composition to moving bed of tablets with concurrent use of facilitate evaporation of solvent. Basic principles involve i) Insulation which influences the release pattern as little as possible and does not markedly change the appearance. application heated air to

ii) iii)

Modified release with specific requirement and release mechanism adapted to body function in the digestive tract. Colour coating which provides insulation or is combined with modified release coating.

Type of tablet coating process

Sugar coating Compressed tablets may be coated with coloured or uncoloured sugar layer. The coating is water soluble and quickly dissolves after swallowing. The sugarcoat protects the enclosed drug from the environment and provides a barrier to objectionable taste or order. The sugar coat also enhances the appearance of the compressed tablet and permit imprinting manufacturings information. Sugar coating provides a combination of insulation, taste masking, smoothing the tablet core, colouring and modified release. The disadvantages of sugar coating are the time and expertise required in the coating process and thus increases size, weight and shipping costs.

Sugar coating process involves five separate operations:

I.

Sealing/Water proofing: provides a moisture barrier and harden the tablet surface Subcoating: causes a rapid buildup to round off the tablet edges. Grossing/Smoothing: smoothes out the subcoated surface and increases the tablet size to predetermine dimension. Colouring: gives the tablet its colour and finished size. Polishing: produces the characteristics gloss.

II. III. IV. V.

Film coating:A more recent method of coating the tablet is film coating. Although the film coated tablets are possibly less elegant in the appearance but they are considered more satisfactory than sugar coated tablets because in film coating various steps like water proofing sub coating and smoothing are unnecessary their by the coating time reduced to a great extent . Ultimately the cost of production is decrease and tablet of better strength are produced. Process description Film coating is deposition of a thin film of polymer surrounding the tablet core. Conventional pan equipments may be used but now a days more sophisticated equipments are employed to have a high degree of automation and coating time. The polymer is solubilized into solvent. Other additives like plasticizers and pigments are added. Resulting solution is sprayed onto a rotated tablet bed. The drying conditions cause removal of the solvent, giving thin deposition of coating material around each tablet core.

Materials used in film coating I. II. III. IV . Film formers, which may be enteric or nonenteric Solvents Plasticizers Colourants

V Opaquant-Extenders
7

VI.

Miscellaneous coating solution components

Enteric coating:This type of coating is used to protect tablet core from disintegration in the acid environment of the stomach for one or more of the following reasons: i)To prevent degradation of acid sensitive API ii) iii) iv) To prevent irritation of stomach by certain drugs like sodium salicylate Delivery of API into intestine To provide a delayed release component for repeat action tablet

Several kinds of enteric layer systems are now available:-

One layer system - The coating formulation is applied in one homogeneous layer, which can be whites-opaque or coloured. Benefit is only one application needed.

Two layer system - To prepare enteric tablets of high quality and pleasing appearance the enteric formulation is applied first, followed by coloured film. Both layers can be of enteric polymer or only the basic layer contains enteric polymer while top layer is fast disintegrating & water-soluble polymer

Ideal properties of enteric coating material are summarized as below

7

i) ii) iii) iv) v) vi)

Resistance to gastric fluids Susceptible/permeable to intestinal fluid Compatibility with most coating solution components and the drug substrate Formation of continuous film Nontoxic, cheap and ease of application Ability to be readily printed

Polymers used for enteric coating are as follow

1. Cellulose acetate phthalate (CAP) 2. Acrylate polymers 3. Hydroxy propyl methyl cellulose phthalate 4. Polyvinyl acetate phthalate

Evaluation of tablets/ standardization of tablets

Non compendial standards
Measurement of mechanical properties is not covered pharmacopoeial monograph. There are also a number of tests frequently applied to tablets for which there are no pharmacopoeial requirement but will form a part of a manufacturers own product specification. Hardness tests/ Crushing strength The test measures crushing strength property defined as the compressional force applied diametrically to a tablet which just fractures it. Among a large number of measuring devices, the most favored ones are Monsanto tester, Pfizer tester, and Strong cobb hardness tester. All are manually used. So, strain rate depends on the
7

operator. Heberlein Schleuniger, Erweka, Casburt hardness testers are motor driven.

Friability
The tablet may well be subjected to a tumbling motion. For example, Coating, packaging, transport, which are not severe enough to break the tablet, but may abrade the small particle from tablet surface. To examine this, tablets are subjected to a uniform tumbling motion for specified time and weight loss is measured. Roche friabilator is most frequently used for this purpose.

Tests for coated tablets:I. Water vapor permeability II. Film tensile strength III. Coated tablet evaluations: i) Adhesion test with tensile-strength tester: Measures force required toe peel the film from the tablet surface. ii) Diametral crushing strength of coated tablet: Tablet hardness testers are used. This test gives information on the relative increase in crushing strength provided by the film and the contribution made by changes in the film composition. iii) Temperature and humidity may cause film defects. Hence studies are to be carried out. iv) Quantification of film surface roughness, hardness, & colour uniformity. Visual inspection or instruments are used. Resistance of coated tablet on a white sheet of paper

In Process Quality Control:The control of the tableting process in production is concerned with the following : I. Weight of tablet Single pan electric balance. II. Crushing strength Controls friability and disintegration time. III. Tablet thickness Very thick tablet affect packaging particularly into blisters. IV. Disintegration time- the disintegration test is performed to find out that within how much time the tablet disintegrates. Generaly the disintigration time for uncoated tablets is 30 mins. And for coated tablets in 1 hr.
7

V. Friability- As a part of Current Good Manufacturing Practice (cGMP), the production run is monitored under control chart. At regular interval (10 15minutes) the operator must sample specified number of tablets, weigh them individually, check thickness, crushing strength and all the properties as mentioned above. The process can be automated and interfaced with printer. Such data promotes process improvement. VI .Dissolution test- the rate of dissolution of a solid drug plays an important role in the absorption and physiological availability of drug in the blood stream. Therefore the determination of dissolution rate of any solid drug is very necessary

COMPARISON OF DIFFERENT PHARMACOPOEIAL QUALITY CONTROL TESTS

PHARMACOPOEIAS BRITISH PHARMACOPOEIA TYPE OF TABLET TESTS TO BE PERFORMED Content of active ingredients For all tablets Disintegration Uniformity of content Labeling Uncoated tablet Effervescent tablet Disintegration test Uniformity of weight Disintegration test Uniformity of weight

Coated tablet Disintegration test Uniformity of weight Gastro resistant tablet Disintegration test

Modified Uniformity of weight release tablet Tablet for use Uniformity of weight in mouth Soluble tablet Dispersible tablet Disintegration test Uniformity of weight Disintegration test Uniformity of dispersion Uniformity of weight Uniformity of container content Uncoated tablet Content of active ingredient Uniformity of weight Uniformity of content Disintegration test

INDIAN PHARMACOPOEIA

Enteric coated Disintegration test tablet Dispersible tablet Effervescent tablet Uniformity of dispersion Disintegration Disintegration/ Dissolution / Dispersion test Bulk density /Tapped density of powder Powder fineness Loss on drying Physical tests Disintegration test applicable to Tablet friability tablet Dissolution test formulation Drug release testing Uniformity of dosage form Container permeation test Labeling of inactive ingredients

Soluble tablet Disintegration test

UNITED STATES PHARMACOPOEIA

Packaging of tablets

Packaging plays an important role in our everyday lives and provides a range of benefits from choice and convenience to ensuring the product arrives safely. Packaging is the name given to the containers in which products are bought, sold and transported, and ranges from cardboard boxes and wooden pallets to plastic bottles and aluminium drink cans.

Benefits of packaging
7

Protection Hygiene & Safety Convenience Choice Preservation Risk elimination

Tablet in Blister Packing

Information

Reduces waste

Packaging is used to protect a product throughout its life: a. Primary packaging is the wrapping or containers handled by the consumer b. Secondary packaging refers to the larger cases or boxes that are used to group quantities of products for distribution and for display in shops
c.

Tertiary packaging refers to the wooden pallets, cardboard and plastic wrapping that is used to group the products into larger loads for transport.

Blister packing:-

Blister pack is a term for several types of pre-formed plastic packaging used for small The two primary components of a blister pack are the cavity or pocket made from a "formable" web, either plastic or aluminium - and the lidding, made from paper, paperboard, plastic or aluminium. The "formed" cavity or pocket contains the product and the "lidding" seals the product in the package.

Strip packing machine is extensively used to pack tablets, capsules, caplets, coated tablets, soft gelatin capsules. The same is also used to pack supari, tobacco, refills, battery cells, mats, bearings, oil seals, steel balls, chewing gum, tofees etc. Features: Suitable for most heat sealable foils like aluminum poly, glassine poly, paper poly etc. All parts are standardised which ensures quick inter changeables. There are 5 different models, capacity ranging from 400 to 2500 tablets per minute. Trouble free smooth operation.

BIBLIOGRAPHY

Carter S.J. Cooper and Gunns Tutorial Pharmacy 1972, 6th edition, The Kothari Book Depot- Mumbai. Gupta A.K, Introduction to Pharmaceutics-I, 2006, 4th edition, CBS Publishers and Distributors, Dariyaganj New Delhi. Indian Pharmacopoeia- Vol. I & II , 1996, Government of India, Ministry of Health and Welfare, The Controller of Publications, Delhi. Lachman leon et-al The Theory and Practice of Industrial Pharmacy1991, 3rd edition,Varghese Publishing House Hind Rajasthan Building, Dadar Mumbai. Subrahmanyam C.V.S. et-al Pharmaceutical Engineering Principles and Practices 2008, Ist edition,Vallabh Prakashan Pitampura, Delhi.

www.pharmpedia.com/org